Grant: Doctoral: Vanier Canada Graduate Scholarships

Type 2 diabetes (T2D) is characterized by high blood sugar due to the reduced ability of the body to respond to insulin and the insufficient release of insulin from pancreatic islets. Youth onset T2D is the fastest growing disease among Indigenous children of Central Canada, the majority being of Oji-Cree heritage. This is a serious concern because 50% of youth living with T2D will develop complications such as kidney failure within 15 years of diagnosis. The combination of a change in the DNA of the HNF-1a gene (HNF-1aG319S) and dramatic dietary changes likely contribute to the recent appearance and immense increase in T2D observed among Oji-Cree youth. As a result, we need to decipher how these environmental and genetic factors interact to affect the development of T2D. HNF-1a is a transcription factor, meaning it works to control the expression of other genes within a cell. We have created the first mouse model reflective of the HNF-1aG319S variant using state-of-the-art gene editing technology. Male and female mice that carry zero, one or two copies of the G319S variant will be fed one of three experimental diets: a standard mouse diet, a diet similar to the traditional Oji-Cree diet, or a diet similar to the modern Oji-Cree diet. We will assess markers of diabetes development including whole-body glucose tolerance and insulin sensitivity from birth to old age. The pancreatic islets will be isolated to define the cellular and gene expression mechanisms through which the G319S variant impairs insulin secretion and pancreas development. This will be the first detailed investigation into the relationship between genetics, diet, and diabetes in the Oji-Cree population. Our study will provide an in-depth description of the cellular pathways that are disrupted due to the G319S variant, as well as their functional impact at a whole-body level. This model will serve as a foundation to develop culturally-appropriate therapeutic strategies in the future.